Alpha-1-Antitrypsin Deficiency: A Misfolded Secretory Glycoprotein Damages the Liver by Proteotoxicity and Its Reduced Secretion Predisposes to Emphysematous Lung Disease Because of Protease-Inhibitor Imbalance

In the classical form of α1-antitrypsin deficiency (ATD) a point mutation leads to protein misfolding such that the mutant protein accumulates in liver cells with a marked decrease in levels of this protein in the blood and body fluids. Because the major function of α1-antitrypsin is inhibition of neutrophil elastase and several other neutrophil proteases, individuals with ATD are susceptible to destructive lung disease/emphysema, now called chronic obstructive pulmonary disease (COPD), by a loss-of-function mechanism in which uninhibited neutrophil proteases destroy the connective tissue matrix of the lung. Homozygous individuals are also susceptible to liver disease by a gain-of-toxic function mechanism triggered by the intracellular accumulation of the misfolded protein. The only therapeutic strategies currently available are protein replacement therapy and lung transplantation for COPD and liver transplantation for the subgroup with progressive liver involvement. New therapeutic strategies that mitigate the intracellular accumulation/proteotoxicity have advanced to clinical trials and corrective genetic strategies are in earlier pre-clinical phases of development.